Exacerbation of type 1 diabetes in mice by bisphenol A and genistein

描述（由申请人提供）：1型糖尿病（T1D）是一种器官特异性自身免疫性疾病，在过去的几十年里，该疾病在全球范围内以每年约3%的速度增长，主要发生在年轻人群中。已经注意到同时增加了对内分泌干扰物（EDs）的暴露，从而提出了可能的因果关系。双酚A （BPA）和染料木素（GEN），前者用于聚碳酸酯塑料的制造，也用于水瓶、食品容器和牙齿填充物中的环氧树脂；后者是大豆食品中普遍存在的一种植物雌激素。越来越多的人担心，豆浆和双酚a（包括含双酚a的奶瓶）联合暴露会改变异种生物代谢和协同作用，因此有必要研究GEN和双酚a在发育型产后T1D中的相互作用。由胸腺中枢耐受性紊乱引起的T细胞活性失调在T1D流行中起关键作用。同卵双胞胎中T1D发病率的不一致也提示表观遗传学在其表现中的作用。BPA和GEN都能失调T细胞活性并引起不适当的表观遗传修饰，支持T1D增加的可能因果作用。研究人员推测，在遗传易感的雌性非肥胖糖尿病小鼠和链脲霉素诱导的雌性糖尿病C57BL/6小鼠中，围产期BPA¿GEN暴露破坏了胸腺免疫耐受，从而加剧了T1D。研究人员认为，这种破坏是通过不适当的表观遗传修饰，使器官在青春期周围为随后的雌激素触发自身免疫做好准备。上述中心假设将在以下两个目标的实验中得到解决：(1)确定围产期暴露于GEN和BPA后成年雌性小鼠T1D的恶化情况及其与胸腺间质微环境和白细胞介素(IL)-17和Foxp3表达的关系；(2)验证产前暴露于GEN和BPA导致胸腺髓质上皮细胞T1D易感基因启动子/增强子区组蛋白翻译后修饰的假设，以及Foxp3和IL-17基因位点DNA甲基化和组蛋白乙酰化的变化。这些目标被设计为现有BPA和GEN发育免疫毒性数据库的重点扩展，以一种共同需要的方式来理解ed如何作为“健康和疾病的发育起源”化合物来增加晚年T1D的风险。表观遗传学疗法，包括全球DNA去甲基化药物，已经转化为改善癌症患者的护理，并表明未来T1D治疗的潜在临床重要性。这种鉴定：1)可能的基因目标

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an organ-specific autoimmune disease that has been showing a disturbing global increase of approximately 3% per year, predominantly in the younger age groups, over the last decades. Parallel increased exposure to endocrine disruptors (EDs) has been noted, resulting in suggestions of possible causality. Two EDs of particular significance due to their abundance are bisphenol A (BPA), used in the construction of polycarbonate plastics as well as epoxy resins found in water bottles, food containers and dental fillings, and genistein (GEN), a prevalent phytoestrogen found in soy food. Growing concerns of altered xenobiotic metabolism and synergistic interaction from combined exposure to soymilk and BPA, including in BPA-laden baby bottles, has warranted the investigation of the interactions between GEN and BPA on development-based postnatal T1D. Dysregulated T cell activity resulting from disturbed thymic central tolerance plays a key role in the T1D epidemic. Discordant T1D incidence among monozygotic twins also suggested a role for epigenetics in its manifestation. BPA and GEN both dysregulate T cell activity and cause inappropriate epigenetic modifications, supporting a possible causal role in increased T1D. The investigators hypothesize that T1D is exacerbated because thymic immune tolerance is disrupted by perinatal BPA ¿ GEN exposure in genetically susceptible female non-obese diabetic mice and streptozotocin-induced female diabetic C57BL/6 mice. The investigators believe this disruption is through inappropriate epigenetic modifications, which prime the organ for subsequent estrogen-triggering of autoimmunity during peripuberty. The above central hypothesis will be addressed in the experiments of the following two Aims: (1) Determine the exacerbation of T1D in adult female mice following perinatal exposure to GEN and BPA, and its relationship to thymic stromal microenvironment and the expression of interleukin (IL)-17 and Foxp3; and (2) Test the hypothesis that prenatal exposure to GEN and BPA causes histone post-translational modifications at the promoter/enhancer regions of T1D susceptible genes in the medullary thymic epithelial cells, and changes of DNA methylation and histone acetylation in Foxp3 and IL-17 gene loci. These aims are designed as a focused expansion of the existing BPA and GEN developmental immunotoxicity database, in a manner collectively required to understand how EDs act as "developmental origins of health and disease" compounds to increase risk of later-life T1D. Epigenetic therapy including global DNA demethylating drugs, has translated into improved care for cancer patients, and suggests potential clinical importance of proposed studies for future T1D treatment. This identification of: 1) possible gene targets that are important in increasing risks; 2) vulnerable periods in life; and 3) environmental factors which through different mechanisms may be driving the immunological processes that lead to T1D is required to make informed decisions regarding intervention studies and produce potential biomarkers for use in subsequent human surveillance studies.